Highlights
– Longitudinal UK registry data from 104 confirmed congenital TTP (cTTP) patients (median follow-up 63 months) demonstrate that regular plasma prophylaxis markedly reduces acute TTP episodes and end-organ events (notably stroke/TIA and renal impairment).
– Despite biochemical and clinical benefits of plasma prophylaxis, many patients continue to experience substantial symptom burden (headache, fatigue, abdominal pain, mood disturbance) and practical problems (infusion reactions and transfusion dependence), prompting transition to recombinant ADAMTS13 in many cases.
– The cohort shows extensive ADAMTS13 allelic heterogeneity (71 variants); N‑terminal variants associate with earlier presentation, highlighting genotype-phenotype correlations relevant to prognosis and counseling.
Background
Congenital thrombotic thrombocytopenic purpura (cTTP), an ultrarare thrombotic microangiopathy, results from bi-allelic pathogenic variants in ADAMTS13, the metalloprotease responsible for cleaving ultra-large von Willebrand factor multimers. Severe inherited deficiency of ADAMTS13 (<10% activity) predisposes to microvascular platelet-rich thrombi, with clinical manifestations ranging from neonatal life‑threatening disease to recurrent episodes of thrombocytopenia, haemolysis, organ ischemia and chronic symptoms between acute events.
Management historically relies on replacement of ADAMTS13 via plasma infusions or plasma exchange; more recently, plasma prophylaxis strategies and recombinant ADAMTS13 products have emerged to reduce event rates and transfusion-associated complications. However, high-quality long‑term outcome data in large, representative cTTP populations have been limited. The UK TTP registry cohort reported by Stubbs and colleagues (Blood 2025) delivers one of the largest longitudinal datasets to date and yields clinically actionable insights on genotype spectrum, prophylaxis effectiveness, residual morbidity and the reasons patients switch to recombinant therapy.
Study design
Stubbs et al. present a longitudinal analysis from the UK TTP registry including 104 confirmed cTTP patients (91 of whom consented to follow-up). The cohort is multiethnic and includes a substantial representation of Black African individuals.
Key elements:
- Population: 104 genetically confirmed cTTP cases (91 with prospective follow-up consent).
- Follow-up: median 63 months (range 1–179 months).
- Assessments: ADAMTS13 genetic variants and location, age at presentation, prophylaxis use (regular plasma-derived replacement), acute TTP episode frequency, incident end-organ events including cerebrovascular events (stroke/TIA) and renal impairment, patient-reported symptom burden and adverse reactions. Transition to recombinant ADAMTS13 and reasons for switching were also recorded.
- Outcomes reported as event rates per follow-up year and pre/post comparisons within the cohort.
Key findings
Genetic heterogeneity and genotype-phenotype signal
The authors identified 71 distinct ADAMTS13 variants across the cohort, underscoring marked allelic diversity in cTTP. A notable genotype-phenotype association was that N‑terminal variants correlated with an earlier age at clinical presentation. While the report does not provide a predictive algorithm, this observation supports that variant location and molecular impact matter for phenotype and may inform counseling, surveillance intensity and early treatment discussions.
Prophylaxis uptake and composition
During the follow-up period, 80.2% of patients received regular prophylaxis using plasma-derived products (most commonly fresh frozen plasma or solvent/detergent-treated plasma), reflecting contemporary UK practice and the long-standing reliance on plasma products for ADAMTS13 replacement.
Reduction in acute episodes
Regular prophylaxis was associated with a marked reduction in post-presentation acute TTP episodes. The annualized acute episode rate decreased from 0.68 episodes per follow-up year without prophylaxis to 0.06 episodes per follow-up year while on prophylaxis. This represents a substantial clinical effect size consistent with the biologic rationale that maintaining ADAMTS13 activity prevents the formation of pathologic ultra-large VWF multimers.
Reduction in end-organ events
Prophylaxis was associated with reduced incident end-organ damage. Cerebrovascular events (stroke/TIA) declined from 19.0% before prophylactic strategy to 1.5% during follow-up with regular prophylaxis. There was also a reduction in new or progressive renal impairment during follow-up among those receiving prophylaxis. These findings indicate that long-term ADAMTS13 replacement not only lowers acute clinical flares but also may prevent cumulative ischemic injury to organs.
Persistent symptom burden despite replacement
Despite these benefits, substantial symptomatology persisted in patients receiving plasma-derived prophylaxis. Reported symptoms included headache (42.6%), fatigue (16.2%), abdominal pain (13.2%), and depression/anxiety (13.2%). These symptoms are clinically important because they impair function, quality of life and may reflect subclinical microvascular disease or other disease-related mechanisms not fully corrected by intermittent plasma replacement.
Safety, complications and drivers for change to recombinant ADAMTS13
Plasma-related adverse issues remained a problem. Infusion reactions and logistical burdens of repeated plasma exposure were important determinants of patient experience. During follow-up, most eligible UK patients transitioned to recombinant ADAMTS13 (rADAMTS13) — 43 patients (58.9%) had switched. The reasons documented for switching were: inadequate symptom control on plasma (53.5%), plasma reactions (30.2%), and concern about subclinical disease activity (16.3%). The switch pattern highlights both clinical and patient-reported drivers in favor of targeted replacement therapy with rADAMTS13.
Interpretation of effect sizes
The magnitude of reduction in acute episode rates and cerebrovascular events while on prophylaxis is clinically meaningful and supports current practice of individualized prophylaxis for patients with recurrent or severe disease. The near tenfold decrease in acute episode rate (0.68 vs 0.06/year) is compelling, though absolute numbers and confidence intervals are not provided in the summary; interpretation should therefore account for registry design and potential confounders (see limitations below).
Expert commentary and mechanistic considerations
The findings align with the biologic expectation that sustained ADAMTS13 activity prevents pathologic VWF multimer–mediated platelet aggregation in the microcirculation. Recurrent microvascular thrombosis is the likely driver of strokes and renal impairment; therefore, prophylactic replacement that maintains trough ADAMTS13 activity should reduce cumulative ischemic injury.
Nevertheless, the persistence of headaches, fatigue and other somatic symptoms despite prophylaxis suggests either incomplete biochemical correction with intermittent plasma (variable trough levels, short ADAMTS13 half-life between infusions) or other mechanisms such as microvascular dysfunction not fully reversed by replacement, comorbidities, or psychosocial factors. Recombinant ADAMTS13 could provide more predictable pharmacokinetics and avoid plasma-associated issues, but long‑term comparative effectiveness and safety data are still accruing.
Limitations and generalizability
Key limitations inherent to registry-based observational work include potential selection bias (patients consenting to follow-up may not fully represent the entire cTTP population), heterogeneity in prophylaxis regimens (dose, interval, product type), and lack of randomized assignment to prophylaxis. Confounding by indication is possible: patients selected for prophylaxis may differ systematically from those not receiving it.
The reductions in event rates are encouraging but should be interpreted cautiously because the pre/post comparisons may be influenced by surveillance intensity, secular improvements in care, and survivorship bias. Detailed pharmacokinetic and ADAMTS13 activity data tied to clinical events would strengthen causal inference but are not detailed in the summary data.
Finally, while the cohort is large for an ultrarare disease and multiethnic (including a substantial Black African group), results reflect UK practice and may differ in regions with different access to plasma products, blood‑product screening, or recombinant therapies.
Clinical implications and future directions
For clinicians managing cTTP, the study reinforces that regular ADAMTS13 replacement (even with plasma-derived products) can markedly reduce acute episodes and end-organ ischemic events and should be considered in patients with recurrent disease or those at high risk for complications. The documented residual symptom burden emphasizes the need to assess patient-reported outcomes systematically and to consider alternative strategies for patients with incomplete symptomatic control or plasma-related complications.
rADAMTS13 represents a promising advance with potential advantages in tolerability and pharmacokinetic predictability. Uptake in this UK cohort reflects real-world drivers: symptom control, infusion reactions, and concerns about subclinical disease. Prospective trials and registry-linked pharmacodynamic studies are needed to compare rADAMTS13 versus plasma prophylaxis for hard clinical endpoints (stroke, renal function decline), patient-reported outcomes, quality of life and long-term safety.
Additionally, the broad allelic spectrum and genotype-phenotype observations suggest utility for early genetic diagnosis, family screening and individualized counseling about prognosis and timing of intervention. Future studies that integrate variant-level functional data with longitudinal clinical outcomes could inform risk stratification algorithms and personalized prophylaxis schedules.
Conclusion
The UK TTP registry longitudinal analysis provides robust real-world evidence that regular plasma-derived ADAMTS13 replacement substantially reduces acute TTP episodes and the incidence of cerebrovascular and renal events in cTTP. However, significant residual symptom burden and plasma-related complications remain important unmet needs and a major reason patients are transitioning to recombinant ADAMTS13. These data support the clinical value of prophylaxis while highlighting the necessity for improved therapies, standardized outcome measures including quality of life, and prospective comparative studies of replacement strategies.
Funding and clinicaltrials.gov
Funding and formal trial registration information are reported in the original publication: Stubbs M et al., Blood 2025. For details on funding sources and protocol-level information, consult the primary article.
References
1. Stubbs M, Keogh L, Gounder P, et al. Long-term follow-up outcomes in congenital thrombotic thrombocytopenic purpura. Blood. 2025 Nov 13;146(20):2457-2463. doi: 10.1182/blood.2025029789. PMID: 40864978.
